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https://doi.org/10.1371/journal.pone.0204853
Title: | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes | Authors: | Wen Wong D.P. Ng M.Y. Leung J.Y. Boh B.K. Lim E.C. Tan S.H. Lim S. Seah W.H. Hu C.Z. Ho B.C. Ng D.H.P. Hagen T. |
Keywords: | andrographolide cullin cullin 3 kelch like ECH associated protein 1 protein RBX1 RING finger protein sulforaphane transcription factor Nrf2 unclassified drug andrographolide carrier protein CUL3 protein, human cullin diterpene KEAP1 protein, human kelch like ECH associated protein 1 NFE2L2 protein, human plant extract protein binding RBX1 protein, human transcription factor Nrf2 Article binding affinity Calymperes erosum Campylopus serratus densitometry Dicranopteris linearis endophyte enzyme activity fern human human cell moss nonhuman Ophioglossum reticulatum Philonotis thwaitesii Phlegmariurus phlegmaria protein binding protein degradation protein expression protein function protein interaction protein localization protein processing protein stability Psilotum nudum Pyrrosia piloselloides Taenitis blechnoides ubiquitination Vesicularia dubyana binding site chemistry drug effect endophyte gene expression regulation HEK293 cell line metabolism secondary metabolism Binding Sites Bryophyta Carrier Proteins Cullin Proteins Diterpenes Endophytes Ferns Gene Expression Regulation HEK293 Cells Humans Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 Plant Extracts Protein Binding Secondary Metabolism Ubiquitination |
Issue Date: | 2018 | Publisher: | Public Library of Science | Citation: | Wen Wong D.P., Ng M.Y., Leung J.Y., Boh B.K., Lim E.C., Tan S.H., Lim S., Seah W.H., Hu C.Z., Ho B.C., Ng D.H.P., Hagen T. (2018). Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes. PLoS ONE 13 (10) : e0204853. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0204853 | Abstract: | The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds. © 2018 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/165895 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0204853 |
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